New Insights in Trigeminal Anatomy: A Double …...Keywords: trigeminal nerve, trigeminothalamic tract, orofacial pain, trigeminal neuropathy, bilateral registration INTRODUCTION Facial

HYPOTHESIS AND THEORYpublished: 10 May 2016

doi: 10.3389/fnana.2016.00053

New Insights in Trigeminal Anatomy:A Double Orofacial Tract forNociceptive InputDylan J. H. A. Henssen 1,2*, Erkan Kurt 2, Tamas Kozicz 1, Robert van Dongen 3,Ronald H. M. A. Bartels 2 and Anne-Marie van Cappellen van Walsum 1

1 Department of Anatomy, Donders Institute for Brain Cognition and Behavior, Radboud University Medical Center, Nijmegen,Netherlands, 2 Department of Neurosurgery, Radboud University Medical Center, Nijmegen, Netherlands, 3 Departmentof Anaesthesiology, Pain and Palliative Care, Radboud University Medical Center, Nijmegen, Netherlands

Edited by:Dave J. Hayes,

University of Toronto, Canada

Reviewed by:Antonio Pereira,

Federal University of Rio Grande doNorte, BrazilChia-shu Lin,

National Yang-Ming University,Taiwan

Mojgan Hodaie,University of Toronto, Canada

*Correspondence:Dylan J. H. A. Henssen

[email protected]

Received: 23 December 2015Accepted: 26 April 2016Published: 10 May 2016

Citation:Henssen DJHA, Kurt E, Kozicz T, van

Dongen R, Bartels RHMA and vanCappellen van Walsum A-M (2016)New Insights in Trigeminal Anatomy:

A Double Orofacial Tract forNociceptive Input.

Front. Neuroanat. 10:53.doi: 10.3389/fnana.2016.00053

Orofacial pain in patients relies on the anatomical pathways that conduct nociceptiveinformation, originating from the periphery towards the trigeminal sensory nucleuscomplex (TSNC) and finally, to the thalami and the somatosensorical cortical regions.The anatomy and function of the so-called trigeminothalamic tracts have beeninvestigated before. In these animal-based studies from the previous century, theintracerebral pathways were mapped using different retro- and anterograde tracingmethods. We review the literature on the trigeminothalamic tracts focusing on theseanimal tracer studies. Subsequently, we related the observations of these studiesto clinical findings using fMRI trials. The intracerebral trigeminal pathways can besubdivided into three pathways: a ventral (contralateral) and dorsal (mainly ipsilateral)trigeminothalamic tract and the intranuclear pathway. Based on the reviewed evidencewe hypothesize the co-existence of an ipsilateral nociceptive conduction tract to thecerebral cortex and we translate evidence from animal-based research to the humananatomy. Our hypothesis differs from the classical idea that orofacial pain arises onlyfrom nociceptive information via the contralateral, ventral trigeminothalamic pathway.Better understanding of the histology, anatomy and connectivity of the trigeminal fiberscould contribute to the discovery of a more effective pain treatment in patients sufferingfrom various orofacial pain syndromes.

Keywords: trigeminal nerve, trigeminothalamic tract, orofacial pain, trigeminal neuropathy, bilateral registration

INTRODUCTION

Facial pain can be caused by many factors. One of the most severe and highly incapacitatingconditions in which pharmacological treatments have an insufficient effect, are calledtrigeminal neuropathies, clinically often known as trigeminal neuralgia (Tsubokawa et al.,1991, 1993; Nguyen et al., 2000; Raslan et al., 2011; Slotty et al., 2015; Kolodziej et al., 2016).

Abbreviations: ACC, Anterior cingulate cortex; BOLD, Blood oxygen level dependent; CS, Caudal subnucleus;DTI, Diffusion tensor imaging; DW-MRI, Diffusion weighted magnetic resonance imaging; fMRI, Functionalmagnetic resonance imaging; IS, Interpolar subnucleus; MeN, Mesencephalic nucleus; MoN, Motor nucleus; OS,Oral subnucleus; PAG, Periaquaductal gray; PO, Posterior nucleus; PSN, Principal sensory nucleus; RF, Reticularformation; SN, Spinal nucleus; ST, Spinal tract; TSNC, Trigeminal sensory nucleus complex; VPL, Ventralposterolateral nucleus; VPM, Ventral posteromedial nucleus; V1, Ophthalmic nerve; V2, Maxillary nerve; V3,Mandibular nerve.

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Henssen et al. New Insights in Trigeminal Anatomy

Although trigeminal neuropathies were first described morethan 300 years ago, little is known about the relationshipwith the trigeminal nerve itself and the origin of the pain(Burchiel, 2003; Jantsch et al., 2005). In order to gain insight inthe pathophysiology of trigeminal neuropathy, the anatomicalconnections between the trigeminal nerve and the involvedbrain regions seem of great importance. In summary, it isgenerally believed that sensory fibers involved in the conductionof pain and temperature spread over the trigeminal sensorynucleus complex (TSNC) and then cross over to the contralateralthalamus and cerebral cortex (Greenspan and Winfield, 1992;Bushnell et al., 1999; Kanda et al., 2000; Nieuwenhuys et al.,2008). In 2010, however, Nash et al. (2010) reported a bilateralfMRI registration in humans after noxious orofacial stimulation.Twenty-eight human subjects were injected with hypertonicsaline (0.3 ml) into the central belly of the right massetermuscle and into the overlaying skin. Using blood oxygenlevel dependent (BOLD) contrast, a 3T Scanner imaged abilateral fMRI-activation of the thalamus, S1 and S2 corticesafter noxious orofacial stimulation. As an explanation, theauthors hypothesized an extra tract, originating from thetrigeminal nuclei running towards both thalami. However, noanatomical details about topography, explanation or evidencecan be found in the anatomical literature for this hypothesizedextra tract. The aims of this review are: (1) to provide a detailedoverview of existing knowledge of the anatomy and function ofthe trigeminal nerve, its nuclei and its intracerebral pathwaysin animals; (2) to present studies that use functional imaging inthe discussion of cortical representation of pain; and (3) to gainnew insights in trigeminal anatomy in humans by synthesizinganimal-based studies and papers that discuss functional imagingin humans.

ANATOMY OF THE TRIGEMINAL NERVEAND THE TSNC

The extracerebral portion of the three divisions of the trigeminalnerve (V1: ophthalmic division, V2: maxillary division, V3:mandibular division) has been described extensively beforeby many authors (Lang, 1981; Usunoff et al., 1997; Sessle,2000; Go et al., 2001; Williams et al., 2003; Schünke et al.,2006; Nieuwenhuys et al., 2008; Borges and Casselman, 2010;Sabancl et al., 2011; Bathla and Hegde, 2013; Joo et al.,2014; Marur et al., 2014). The three main divisions fuse atthe trigeminal ganglion, which divides into motor and sensorrootlets. These rootlets enter the lateral pons and fibers coursetowards the four trigeminal nuclei: the (1) Principal SensoryNucleus (PSN); (2) Mesencephalic Nucleus (MeN); (3) SpinalNucleus (SN); and (4) Motor Nucleus (MoN; Figure 1). ThePSN and the SN together are also called the trigeminal sensorynuclear complex (TSNC) and are held responsible for theconduction of pain and temperature information (Matsushitaet al., 1982).

The trigeminal nuclei have been well described by manyauthors (Ramon y Cajal, 1909; Meessen and Olszewski, 1949;Olszewski, 1950; Astrom, 1953; Taber, 1961; Eisenmann et al.,1963). A histological example of all the trigeminal nuclei,

FIGURE 1 | Schematic overview of the trigeminal nuclei in thebrainstem. MeN, Mesencephalic nucleus; MoN, Motor nucleus; dPSN,Dorsal part of the principal sensory nucleus; vPSN, Ventral part of the principalsensory nucleus; OS, Oral part of the spinal nucleus; IS, Interpolar part of thespinal nucleus; CS, Caudal part of the spinal nucleus; PAG, Periaquaductalgray; which receives afferents and courses more cranially as the intranucleartract. V, Trigeminal nerve; VII, Facial nerve; VIII, Vestibulocochlear nerve;IX, Glossopharyngeal nerve; X, Vagus nerve.

except the SN, is presented in Figure 2. This histologicalblockface was obtained from the unpublished materials fromMollink et al. (2015) and with consent of the authors adaptedand published here. The literature concerning the TSNC, issummarized below. The PSN or pontine nucleus of the trigeminalnerve is located dorsolaterally to the motor nucleus of thetrigeminal nerve in the pons. Its afferent fibers contribute tothe perception of discriminative sensations. The termination






FIGURE 2 | Histological example of the anatomy of the trigeminal sensory nucleus complex (TSNC). Histological section stained for myelin with themodified Heidenhain-Woelcke stain at different levels of the cerebellum and the pons. The unstained areas are recognized as nuclei. CN V, Trigeminal nerve;MeN, Mesencephalic nucleus; PSN, Principal sensory nucleus of the trigeminal nerve; MoN, Motor nucleus of the trigeminal nerve. ∗Decussating fibers of thetrigeminal nucleus. The spinal nucleus is not visible is this section. Unpublished data, published with consent of Mollink et al. (2015).

of these afferent fibers can be divided into a ventral anda dorsal projection site within the PSN. The PSN in thecat is a compact formation and consists of different shapesof neurons (round, stellar and triangular types; Gobel andDubner, 1969). According to Kiknadze et al. (2001) however,the subdivision of the PSN into a ventral and dorsal partis arguable. Analysis of their data shows different-sized anddifferent-shaped neurons throughout the entire nucleus, at equalfrequencies. The SN is located medially to the descending spinaltract (ST) which is located in the dorsolateral region of thebrainstem. The ST extends from the trigeminal entry zone(middle pons) to the third cervical spinal cord segment. TheSN therefore is oriented in a longitudinal plane and can besubdivided into three subnuclei: the caudal (CS), interpolar(IS) and oral (OS) subnucleus. The CS extends from C3 tothe obex and seems consistent with the dorsal horn of thecervical spinal cord. Due to this consistency, the subdivisioninto lamina according to Rexed (1952, 1954) can be used.

Trigeminothalamic fibers are found in the layers I, V andVI of the CS and are thought to provide the anatomical andphysiological substrate for pain and temperature perception inthe facial region (Dubner et al., 1978). The IS on the otherhand can be found in between the CS end of the obex andthe CS part of the motor nucleus of the facial nerve. Themedial and rostral borders have been described to be difficultto recognize under the light microscope (Capra and Dessem,1992). The exact function remains unclear, but it is knownthat the IS enlarges when the vibrissae in rodents are welldeveloped and therefore have a heavy central representation.The IS can be subdivided into different regions, receiving inputfrom different terminal branches of the trigeminal nerve. Thedorsolateral region receives input from the auriculotemporalnerve, whereas the ventrolateral region is the termination zoneof the other ophthalmic and maxillary branches (Jacquin et al.,1983; Capra and Dessem, 1992). The OS or rostral subnucleusextends from the CS pole of the facial motor nucleus to the






FIGURE 3 | Anatomy of the different trigeminal nuclei that are part ofthe TSNC. dPSN, Dorsal part of the principal sensory nucleus; vPSN, Ventralpart of the principal sensory nucleus; OS, Oral part of the spinal nucleus;IS, Interpolar part of the spinal nucleus; CS, Caudal part of the spinal nucleus;ST, Spinal tract; PAG, Periaquaductal gray; which receives afferents andcourses more cranially as the intranuclear tract. V, Trigeminal nerve; VII, Facialnerve; VIII, Vestibulocochlear nerve; IX, Glossopharyngeal nerve; X, Vagusnerve.

CS part of the motor nucleus of the trigeminal nerve (Crosbyand Yoss, 1954). This subnucleus can be subdivided into alateral and medial part. The medial subdivision receives afferentsfrom intraoral structures, whereas the lateral part of the OSregisters information from the dorsal structures of the face andthe vibrissae (Eisenmann et al., 1963). Figure 3 recapitulatesthe anatomy of the different trigeminal nuclei that are part ofthe TSNC.

INTRACEREBRAL ANATOMY OF FIBERSORIGINATING FROM THE TSNC

Efferents from the PSNWallenberg (1905) dissected the brains of rabbits and observeduncrossed trigeminothalamic fibers, sprouting from the dorsalpart of the PSN. After the example of Wallenberg (1905)others mentioned this ipsilateral circuit as well (Economo,1911; Woodburne, 1936; Papez and Rundles, 1937; Walker,1939; Papez, 1951; Carpenter, 1957) . Torvik (1957) studied theascending pathways of the trigeminal nerve by means of a partialor complete transection of the rostral brains of 22 kittens andretrograde cellular alterations in the TSNC. It was concluded thatfrom the PSN almost all fibers projected to one of both thalamiand that these projections were both contralateral as ipsilateral.Smith (1975) carried out a partial unilateral stereotactic lesion ofthe PSN in cebus and rhesus monkeys and found a ventromedialdecussation of fibers at the level of the pontine tegmentum and adorsal collection of axons that form a smaller trigeminothalamicprojection, originating from the dorsal one-third of the PSN. Noneurons from the PSN appeared to project to the spinal cord(Matsushita et al., 1982). Matsushita et al. (1982) also used theretrograde horseradish peroxidase technique and injected it intothe posterior ventral nucleus of the thalamus. A large numberof neurons were observed in the ventral segment of the PSNand the IS of the SN on the contralateral side, whereas on theipsilateral side, the dorsal aspect of the PSN was marked afterinjection. Rausell and Jones (1991) bilateral afferents to the VPM,originating from both the ipsilateral and the contralateral PSNusing an anterograde tracing study in 3 cynomolgous monkeys(Macaca fascicularis). Table 1 summarizes the mentioned tracingstudies in animals. Figure 4 depicts the trigeminothalamic tractssprouting from the PSN.

Efferents from the SNGanchrow (1978) injected the CS of the SN with tritiated aminoacids in the squirrel monkey and found that the efferents fromthe CS had a contralateral projection to the VPM. Also, bilateralconnections were observed to the mediodorsal nucleus (MD),together with ipsilateral connections between the PSN and theCS of the SN. Burton et al. (1979) studied the projections fromthe CS of the spinal trigeminal complex with retrograde andanterograde axonal transport techniques in cats. Projectionsto the thalamus were both bilaterally to a dorsomedial regionof the VPM as well as contralaterally to the main part ofthe VPM and PO (posterior nucleus) of the thalamus. Künzle(1998) a weak bilateral projection from the CS of the SNin the hedgehog tenrec (Echinops telfairi) after injection oftrigeminal subdivisions with wheat germ agglutinin conjugatedto horseradish peroxidase, biotinylated dextran amine and asolution of radioactive amino acids. There was little evidencefor a trigeminal projection to the intralaminar nuclei but therewas a distinct projection to the contralateral zona incerta of thethalamus. Furthermore, Ikeda et al. (1982) described intranuclearascending fibers originating from the IS of the cat, after applyinginjections into the SN. The OS of the SN has been described






TABLE 1 | Tracing studies of the principal sensory nucleus (PSN).

Reference Species Tracing technique Anatomical site of lesion/injection

Wallenberg (1905) Rabbit Marchi method after lesion PSNEconomo (1911) Macaque monkey Degeneration PSNWoodburne (1936) Series of vertebrates Chroom silver preparation after sectioning Section stainingWalker (1939) Rhesus monkey Marchi method PSNPapez (1951) Series of quadrupeds Weigert-Pal method Section stainingCarpenter (1957) Rhesus monkey Marchi method after lesion SCP/MesencephalonTorvik (1957) Cat Degeneration after lesion PSNSmith (1975) Cebus monkey Variety of Nauta silver PSN

Rhesus monkey impregnationsMatsushita et al. (1982) Cat Horseradish peroxidase Posterior ventral nucleus of the thalamusRausell and Jones (1991) Cynomolgus monkey Horseradish peroxidase; Anterograde: CS

Germ agglutin-conjugated horseradish peroxidase; Retrograde: S1-cortex, facial areaSolution of 5% fast blue

PSN, Principal sensory nucleus; SCP, Superior cerebellar peduncle.

to be consistent with the PSN. Efferents originating from theOS of the SN cross over to the contralateral VPM as a partof the trigeminal lemniscus (Nieuwenhuys et al., 2008). Thiswould result in the trigeminothalamic tract sprouting fromthe SN as depicted in Figure 5. Furthermore, Panneton andBurton (1982) injected retrograde horseradish peroxidase intothe rostral trigeminal region and showed that neurons in alllaminae, however mainly III and IV of the medullary dorsalhorn, project through an intranuclear pathway. Within layerIII and IV orofacial fibers converge into their separate nuclei.Also, layer III and IV contain, next to orofacial fibers andtrigeminal nuclei, many interneurons that can be responsiblefor the intranuclear pathway (Dubner et al., 1978). A thirdtract therefore can be described, the so-called intranuclear tractrunning towards or within the PAG from the IS and CS of theSN. This would result in the trigeminothalamic tract as depictedin Figure 6.

Table 2 provides an overview of the mentioned tracingstudies.

FUNCTION OF THE DORSALTRIGEMINOTHALAMIC TRACT

Although the trigeminothalamic connections and origins haveextensively been described, little is known about the cells givingrise to these tracts. The dorsal trigeminothalamic tract in animals(cats and monkeys) consists of fibers originating from thedorsal PSN and the CS and OS of the SN (Burton and Craig,1979; Matsushita et al., 1982; Nieuwenhuys et al., 2008). Thisis summarized in Figure 7. The dorsal PSN receives afferentsoriginating from the oral cavity, hence it is associated with theintraoral sensitivity (Shigenaga et al., 1986). Takemura et al.(1993) by studying the afferent axons from the lower andupper teeth. They found that these fibers project to the PSNin monkeys. According to some authors, the PSN also receivesmechanoreceptive afferents from the intraoral cavity (Zeiglerand Witkovsky, 1968; Silver and Witkovsky, 1973; Kishida et al.,1985; Dubbeldam, 1998). In line with these studies, bird speciesthat rely on tactile information while feeding, the complete PSNseems to be enlarged (Gutiérrez-Ibáñez et al., 2009). Shigenaga

et al. (1986) showed that in cats, the branches supplying theanterior face, i.e., the frontal, infraorbital and mental nerves, alsoterminate in the ventral PSN. Furthermore, the alveolar (superiorand inferior), buccal, lingual and pterygopalatine branches,responsible for the intraoral sensitivity, terminate not only indifferent areas of the PSN but also in the OS and IS of the SN.The IS of the SN also receives input from the anterior face regionand the auriculotemporal, corneal, mylohyoid, and zygomaticafferent nerve fibers (Shigenaga et al., 1986). The projecting cellsfrom the CS of the SN are held responsible for the transmissionof pain and temperature from the orofacial region. However,dental pulp afferents projecting to the OS of the SN have alsobeen described (Burton and Craig, 1979; Takemura et al., 1993).The afferents of the OS of the SN are described to conveynoxious information after mechanical stimulation (Woda et al.,1977), but the OS has also been described as a CS extensionof PSN (Eisenmann et al., 1963; Burton et al., 1979). Othersdescribed that the terminals from both the upper and lowerpulpal afferents formed a connection between the PSN and theOS of the SN (Takemura et al., 1993). The IS and CS also receiveafferents from the intra-oral cavity, though this projection isless dense compared to that of the PSN and the OS of the SN(Takemura et al., 1993). Therefore, the exact function of theseseparate subnuclei remains unclear. However, most assume thatthe ipsilateral, dorsal trigeminothalamic tract is responsible forproprioceptic sensorical information, it seems logical to assumethat both the SN and the PSN receive pain, temperature andmechanoreceptive stimuli from the head and intraoral cavity.

FUNCTION OF THE CONTRALATERAL,VENTRAL TRIGEMINOTHALAMIC TRACT

The ventral trigeminothalamic tract, as depicted in Figure 8,consists of fibers originating from the ventral PSN, CS and ISof the SN. The fibers from this ventral tract decussate alongthe medial border of the medial lemniscus and are thereforealso called the trigeminal lemniscus (Torvik, 1957; Smith, 1975;Matsushita et al., 1982; Nieuwenhuys et al., 2008). The ventraltrigeminothalamic tract is held responsible for the conduction ofvital information. The function of the various nuclei has been






FIGURE 4 | Anatomy of the trigeminothalamic tracts sprouting fromthe principal sensory nucleus within the brainstem towards thediencephalon. dPSN, Dorsal part of the principal sensory nucleus;vPSN, Ventral part of the principal sensory nucleus; OS, Oral part of the spinalnucleus; IS, Interpolar part of the spinal nucleus; CS, Caudal part of the spinalnucleus; ST, Spinal tract; PAG, Periaquaductal gray; which receives afferentsand courses more cranially as the intranuclear tract. V, Trigeminal nerve;VII, Facial nerve; VIII, Vestibulocochlear nerve; IX, Glossopharyngeal nerve;X, Vagus nerve. ∗Dorsal trigeminothalamic tract; ∗∗Ventral trigeminothalamictract.

studied intensively before. The PSN is believed to be mainlyinvolved in the conduction of tactile sensations and movementor position sense (Kruger, 1979). However, Kiknadze et al. (2001)showed that the same nucleus is also involved in the processingof orofacial and dental pain in cats. According to Shigenaga et al.(1986) the IS of the SN also receives input from the anterior

FIGURE 5 | Anatomy of the trigeminothalamic tracts sprouting fromthe spinal nucleus within the brainstem towards the diencephalon.dPSN, Dorsal part of the principal sensory nucleus; vPSN, Ventral part of theprincipal sensory nucleus; OS, Oral part of the spinal nucleus; IS, Interpolarpart of the spinal nucleus; CS, Caudal part of the spinal nucleus; ST, Spinaltract; PAG, Periaquaductal gray; which receives afferents and courses morecranially as the intranuclear tract. V, Trigeminal nerve; VII, Facial nerve;VIII, Vestibulocochlear nerve; IX, Glossopharyngeal nerve; X, Vagus nerve.∗Dorsal trigeminothalamic tract; ∗∗Ventral trigeminothalamic tract.

orofacial region and several trigeminal peripheral branches. Aswe know from Sjögvist’s tractotomy, the CS plays an importantrole in the transmission of vital information (Sjöqvist, 1938).These results would suggest that the ventral trigeminothalamictract plays an important role in the contralateral registration oforofacial nociception, as suggested before by others (Sessle, 2000;Nieuwenhuys et al., 2008).






FIGURE 6 | Anatomy of the intranuclear tract within the brainstem.dPSN, Dorsal part of the principal sensory nucleus; vPSN, Ventral part of theprincipal sensory nucleus; OS, Oral part of the spinal nucleus, IS, Interpolarpart of the spinal nucleus; CS, Caudal part of the spinal nucleus; ST, Spinaltract; PAG, Periaquaductal gray; which receives afferents and courses morecranially as the intranuclear tract. V, Trigeminal nerve; VII, Facial nerve; VIII,Vestibulocochlear nerve; IX, Glossopharyngeal nerve; X, Vagus nerve.

ACTIVATION OF BRAIN REGIONS INRESPONSE TO OROFACIAL NOXIOUSSTIMULATION

Pain, including that of orofacial origin, can be mediatedby two systems. The medial system is composed of limbicstructures and the anterior cingulate and insular cortices and isresponsible for the emotional-affective and cognitive-behavioraldimensions of pain (Kulkarni et al., 2005; Wiech et al., 2006).The lateral pain network consists of the lateral spinothalamic

tract, the VPL or VPM of the thalamus and the S1 cortexand processes the sensory-discriminative components of pain(Kenshalo et al., 1988; Bushnell and Duncan, 1989; Bushnellet al., 1999). The main components of the acute pain networkare the prefrontal, M1, S2, anterior cingulate and insular cortices,the thalamus, supplementary motor areas, amygdala, PAG andbasal ganglia (Apkarian et al., 2005). According to classicalknowledge, it would be logical to assume that contralateralactivation of the lateral system in response to unilateral noxiousstimulation would occur. Surprisingly, according to Peyronet al. (2000) bilateral hemodynamic responses to acute noxiousstimuli were observed in the thalamus and anterior cingulate,insular and SII cortices. An activation of S1, prefrontal andposterior parietal cortices, the striatum, cerebellum, PAG andsupplementary motor areas was observed contralateral to thestimulus (Peyron et al., 2000). Bingel et al. (2004a,b) publisheda bilateral somatotopic cortical registration in event relatedfMRI after painful stimulation of the hand and foot. Touchlesslaser pain stimuli were applied to the dorsum of the hand andfoot after which the neuronal response was measured usingBOLD fMRI. In general, Bingel et al. (2004a,b) concluded thatipsilateral activity of S1 could be the result of an uncrossedipsilateral tract or transcallosal excitatory pathways. Farrell et al.(2005) reviewed the literature on upper extremity noxiousstimulation and showed a predominant contralateral activationof the anterior cingulate cortex (ACC), lentiform nucleus andthe S1, S2 and M1 cortices, however the included reportsdiscussed various activation patterns of cortical and subcorticalstructures. An ispilateral activation of the midbrain was alsoobserved. The insular cortex, thalamus, cerebellum, premotorareas and inferior parietal lobule were regions that showedbilateral activation after noxious stimulation of the upperextremity.

Taking orofacial pain into account, in May et al. (1998)injected capsaicin in the foreheads of seven healthy volunteers.May et al. (1998) showed a bilateral activation of the cerebellumand the anterior insula and observed ipsilateral activationof the ACC and contralateral activation of the thalamus.DaSilva et al. (2002) showed an ipsilateral activation of theSN in patients that underwent noxious thermal stimulationof the skin of the trigeminal areas (V1, V2 and V3). Also,DaSilva et al. (2002) showed a contralateral activation ofthe thalamus and S1 cortex after stimulation. Brooks et al.(2005) showed a bilateral activation of the anterior insula,S2 and a contralateral activation of the posterior insulaafter noxious thermal stimulation of the face, hand or foot.When stimulating the face or hand, thalamic activity wasalso observed. Jantsch et al. (2005) discussed a bilateral fMRIactivation of the S1 cortices after painful dental stimulationin eight healthy subjects. Interestingly, Jantsch et al. (2005)also mention a significant increase of BOLD-activation inthe ipsilateral hemisphere after stimulation for which theydo not give any explanation. Jantsch et al. (2005) that acomplex cortical network must be responsible for a bilateralactivation after orofacial stimulation. de Leeuw et al. (2006)observed brain activation with painful hot stimulation of thetrigeminal nerve. In nine participants, the skin overlaying the






left masseter muscle was triggered using thermal stimuli. UsingfMRI, brain activity was registered. Bilateral activation wasseen in the ACC, insula and thalamus. Ettlin et al. (2009)reported that bilateral non-nociceptive orofacial mechanicalstimulation can provoke a bilateral activation of the insularcortex, whereas the S1-cortex was rarely activated. In thesame year, Nash et al. (2009) investigated nociception in 30humans (22 males, 19–52 years) using painful saline injectionsin the right masseter muscle. Both cutaneous and musclenociceptive input activated the CS and OS subdivision ofthe SN. However, cutaneous nociceptive stimulation evoked alarge response within the IS part of the SN, whereas musclenociception was registered in the PSN. Weigelt et al. (2010)studied thirteen healthy volunteers that underwent stimulationof the dental pulp with a constant current tooth stimulator.After stimulation, they reported a bilateral activation of the S1,S2, the medial dorsal nuclei of the thalamus, insular cortices,ACC and precentral areas such as M1 as seen on fMRI. Theinformation of the studies that discuss orofacial pain is presentedin Table 3.

When investigated, the S2, insular and cingulate corticesseemed to be part of a bilateral projection system. Otherstructures, such as the thalamus, S1 cortex and the precentralgyrus, were also involved in the bilateral pain registration(Jantsch et al., 2005; de Leeuw et al., 2006; Staud et al.,2007; Cole et al., 2010; Weigelt et al., 2010). Nevertheless,Brügger et al. (2011) subdivided three lateralization patternsin the brain related to processing dental pain: (1) hemisphericlateralization irrespective of side of stimulation; (2) structureswith predominant contralateral activation; and (3) structuresshowing hemispheric dominance and predominant contralateralactivation. Pattern 1 shows that the right hemispheric effectis stronger to the cerebellar lobes and the parahippocampalarea. The left hemispheric effect on the other hand is strongerto the putamen, pregenual, posterior and anterior cingulatecortices and supramarginal area. The second pattern shows fivebrain areas that are predominantly contralateral: the S1-cortex,thalamus, posterior insula, amygdala, and subcentral area. Thesubcentral area also shows lateralization to one hemisphereaccording to pattern 3. Also, they observe an activation ofthe contralateral amygdala in response to noxious dentalstimulation.

DISCUSSION

We reviewed in animals that the somatosensory fibers of thefifth cranial nerve are distributed over the TSNC. From thesenuclei, three tracts can be recognized. From the ventral part ofthe PSN, a large crossed tract, the trigeminal lemniscus or theventral trigeminothalamic tract arises. This tract also receivesefferents originating from the OS and IS of the SN. Fromthe dorsal part of the PSN arises the dorsal trigeminothalamictract, which also consists out of fibers from both the contra-and ipsilateral SN. Both tracts run to the thalamus, the VPL-region in specific. A third tract can be observed, originatingfrom the distal two thirds of the SN. Fibers of this intranucleartract course into the PAG (Wallenberg, 1905; Kohnstamm,

1910; Economo, 1911; Woodburne, 1936; Papez and Rundles,1937; Walker, 1939; Papez, 1951; Torvik, 1957; Carpenter, 1957;Smith, 1975; Dubner et al., 1978; Ganchrow, 1978; Burton et al.,1979; Ikeda et al., 1982; Matsushita et al., 1982; Panneton andBurton, 1982; Rausell and Jones, 1991; Nieuwenhuys et al.,2008; Negredo et al., 2009; Figure 9). Although the mentionedipsilateral tract has been described before, it has never beenhypothesized to play a prominent role in the conduction ofnoxious stimulation. A full understanding of brain activationin response to nociceptive information is limited by thecomplexity of the multidimensional character of pain and thepain experience. Lateralization of the cortical areas involved inthe medial pain system that seem predominantly active and arenot influenced by the side of stimulation are the different partsof the cingulate gyrus (Brügger et al., 2011). This predominantactivation could explain why fMRI studies show in some casesan ipsilateral activation. When the left cingulate gyrus getsactivated after subjects are stimulated on the left side of thebody, this may appear to be an ipsilateral activation pattern.Nevertheless, bilateral activation of the cingulate gyri has alsobeen observed after unilateral noxious stimulation (Jantsch et al.,2005). The robust contralateral activation of the amygdala canonly be speculated about. A high emotional value attributed toorofacial/dental pain could be one of the factors involved, but theemotional aspect of this kind of pain or noxious stimuli has neverbeen investigated (Brügger et al., 2011). Even so, lateralizationof the amygdala turns out to be inconsistent throughout humanliterature (Bingel et al., 2002; Bornhövd et al., 2002; Brüggeret al., 2011). The subdivisions of the insular cortices showed asubdivision in activation.When bilateral activation was reported,this concerned mainly the anterior insular cortex (May et al.,1998; Jantsch et al., 2005). Contralateral activation was mainlyseen in the posterior insular cortex (Brooks et al., 2005; Jantschet al., 2005; Brügger et al., 2011). The posterior insular cortex ispreferentially connected to other lateral structures, such as theS1 and S2 cortices (Wiech et al., 2014). The other structuresof the lateral pain system are also predominantly contralateralaccording to Brooks’s (2005) and Brüggers’s (2011) studies butthis is contradicted by various reports discussing a bilateralactivation (de Leeuw et al., 2006; Nash et al., 2010; Weigeltet al., 2010). The activation of the ipsilateral S1 cortex is alsoheld implausible, according to Brügger et al. (2011), but otherreports do state a bilateral activation of S1 in response to noxiousstimulation of the orofacial region (Bingel et al., 2004b; Jantschet al., 2005; Nash et al., 2010; Weigelt et al., 2010; Brüggeret al., 2011). The findings (Bingel et al., 2004b; Jantsch et al.,2005; Nash et al., 2010) could be in agreement with the resultsfrom animal-based studies about the intracerebral pathways.When we focus on facial pain, a double trigeminothalamictract could be the answer to this clinical question, if boththe ventral and dorsal trigeminothalamic tract are capable ofnociceptive conduction. Another anatomical solution can befound in the transcallosal pathways. Nevertheless, this seemsimplausible bearing in mind the study of Stein et al. (1989)in which they investigated the pain perception of a split-brainpatient after high intensity noxious stimulation was applied tothe foot.






TABLE 2 | Tracing studies of the spinal nucleus (SN).

Reference Species Tracing technique Anatomical site of lesion/injection

Ganchrow (1978) Squirrel monkey Degeneration after lesion; Injection with tritiatedamino acids

CS

Burton and Craig (1979) Cat and Cynomolgus Injection with horseradish peroxidase Ventroposterior nucleus of thethalamusmonkey

Burton et al. (1979) Cat Injection with mixture of amino acids; Injection withhorseradish peroxidase

Anterograde: CSRetrograde: ventroposterior nucleusof the thalamus

Ikeda et al. (1982) Cat Injection with horseradish peroxidase ISPanneton and Burton (1982) Cat Injection with horseradish peroxidase Rostral trigeminal regionKünzle (1998) Hedgehog tenre Injection with a mixture of wheat germ agglutinin

conjugated to horseradish peroxidase, biotinylateddextran amine and a solution of radioactiveaminoacids

SN and PSN

Negredo et al. (2009) Sprague-Dawley rat Injection with dextran amine Thalamus

CS, Caudal subnucleus; IS, Interpolar subnucleus; SN, Spinal nucleus; PSN, Principal sensory nucleus.

TABLE 3 | Synopsis of activated brain areas after noxious stimulation.

Reference Site of Medial dorsal S1 S2 ACC Insular cortical Precentralstimulation thalamus regions gyrus

May et al. (1998) Subcutaneous capsaicininjection into the forehead

Contralateral N/A N/A Ipsilateral BilateralB N/A

DaSilva et al. (2002) Cutaneous thermal stimulationof right V1 region

Contralateral Contralateral N/A N/A N/A N/A

Cutaneous thermal stimulationof right V2 region


Cutaneous thermal stimulationof right V3 region


Brooks et al. (2005) Cutaneous thermal stimulationof the area below the rightlower lip

Small N/A Bilateral N/A ContralateralD N/AactivationsE

Cutaneous thermal stimulationof the dorsum of the right hand

Small N/A Bilateral N/A ContralateralD N/AactivationsE

Cutaneous thermal stimulationof the dorsum of the right foot

N/A N/A Bilateral N/A ContralateralD N/A

Jantsch et al. (2005) Pneumatic mechanicalstimulation of the middlephalanx

N/A ContralateralA Bilateral Bilateral Bilateral Contra-lateral

Constant electrical dentalstimulation

N/A Bilateral Bilateral Bilateral Bilateral Contra-lateral

de Leeuw et al. (2006) Cutaneous thermal stimulationof the skin area overlying the leftmasseter muscle

Bilateral Contra-lateral N/A Bilateral Bilateral Ipsilateral

Ettlin et al. (2009) Electrical dental stimulation ofone randomly selected caninewith randomized intervals

N/A N/A N/A Small Small SmallactivationsE activationsB,E activationsE

Nash et al. (2010) Subcutaneous hypertonic salineinjection into the skin overlyingthe right masseter muscle andinto the central belly of the rightmasseter muscle

Bilateral Bilateral Bilateral N/A N/A N/A

Weigelt et al. (2010) Constant electrical pulpalstimulation

Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral

N/A, not available from full text; AHand-area on S1; BAnterior insular cortex; CMedial insular cortex; DPosterior insular cortex; EAuthor does not specify the results.

Limitations in the functional imaging of pain are:(1) anticipation of pain; (2) attentional modulation; and(3) emotional accounts of pain. The anticipation of pain isknown to activate several brain regions, including the ACC,

cerebellum, ventral premotor and ventromedial prefrontalcortex, the PAG and hippocampus (Hsieh et al., 1999; Ploghauset al., 1999, 2001, 2003; Bantick et al., 2002). Brügger et al.(2011) study does indeed show that, when anticipation is ruled






FIGURE 7 | Anatomy of the dorsal trigeminothalamic tract within thebrainstem towards the diencephalon. dPSN, Dorsal part of the principalsensory nucleus; vPSN, Ventral part of the principal sensory nucleus; OS, Oralpart of the spinal nucleus; IS, Interpolar part of the spinal nucleus; CS, Caudalpart of the spinal nucleus; ST, Spinal tract; PAG, Periaquaductal gray; whichreceives afferents and courses more cranially as the intranuclear tract.V, Trigeminal nerve; VII, Facial nerve; VIII, Vestibulocochlear nerve;IX, Glossopharyngeal nerve; X, Vagus nerve. ∗Dorsal trigeminothalamic tract.

out, the bilateral activation decreases. This decrease in bilateralactivity shows that anticipation of pain causes a bilateral networkto be activated. Nevertheless, when anticipation is ruled out,there still seems to be a bilateral activation of cortical areasinvolved in the lateral pain system. This would suggest that bothsystems (pain and anticipation of pain) play a prominent role inregistration of pain. Secondly, it is well known that pain relatedanxiety and fear are associated with difficulties in attention and

FIGURE 8 | Anatomy of the ventral trigeminothalamic tract within thebrainstem towards the diencephalon. dPSN, Dorsal part of the principalsensory nucleus; vPSN, Ventral part of the principal sensory nucleus; OS, Oralpart of the spinal nucleus; IS, Interpolar part of the spinal nucleus; CS, Caudalpart of the spinal nucleus; ST, Spinal tract; PAG, Periaquaductal gray; whichreceives afferents and courses more cranially as the intranuclear tract.V, Trigeminal nerve; VII, Facial nerve; VIII, Vestibulocochlear nerve;IX, Glossopharyngeal nerve; X, Vagus nerve. ∗∗Ventral trigeminothalamic tract.

result in an increased awareness of pain (Taylor et al., 2015).Chronic lower back pain patients have been shown to displayactivation of the insular cortex, supplementary motor areaand pre-motor area, cerebellum, thalamus, pulvinar, posteriorcingulate cortex, hippocampus, fusiform gyrus and angulargyrus after they saw a picture showing an aversive movement(Shimo et al., 2011). The emotional accounts have been studiedextensively as well. When cued expectation of pain stimuli is






FIGURE 9 | Anatomy of the hypothesized bilateral orofacial painregistration system in humans. dPSN, Dorsal part of the principal sensorynucleus; vPSN, Ventral part of the principal sensory nucleus; OS, Oral part ofthe spinal nucleus; IS, Interpolar part of the spinal nucleus; CS, Caudal part ofthe spinal nucleus; ST, Spinal tract; PAG, Periaquaductal gray; which receivesafferents and courses more cranially as the intranuclear tract. V, Trigeminalnerve; VII, Facial nerve; VIII, Vestibulocochlear nerve; IX, Glossopharyngealnerve; X, Vagus nerve. ∗Dorsal trigeminothalamic tract; ∗∗Ventraltrigeminothalamic tract.

studied, activation of various regions within the salience (insulaand ACC), sensorimotor and attentional control (parietal andfrontal) networks have been described (Yágüez et al., 2005;Carlsson et al., 2006; Seidel et al., 2015). Taking the mentionedregions into account, fMRI studies of the brain can be very usefuland illustrative, but one must be careful when interpreting theseresults.

Lin (2014) states that a critical step in the future offMRI investigations is to understand the chronic dental pain-related anatomy and cortical representations. The potentialfor investigating and understanding chronic orofacial pain ishighlighted by their two major findings. First, the thalamus andS1 cortex were identified as two major sites of neuroplasticityand second, the increased connectivity between the thalamusand the insula. Although some other authors also state that thestandard anatomy can change under the influence of chronicstimulation, such as pain (Wilcox et al., 2013, 2015), it seemslogical to assume that orofacial pain is bilaterally registered inhealthy humans as well, according to other investigations (Bingelet al., 2004b; Jantsch et al., 2005; de Leeuw et al., 2006; Staudet al., 2007; Cole et al., 2010; Nash et al., 2010; Weigelt et al.,2010). In order to gain more insight in the normal connectivityfrom the orofacial region and the related cortical areas, wesubsequently make some proposals for future investigations. Apost-mortem diffusion tensor imaging (DTI) study based on adiffusion weighted MRI (DW-MRI) scan could contribute toour insights in the trigeminal fibers, because this is currentlythe only capable method of mapping the detailed architectureof white matter fibers in human brain specimens (Jones et al.,2013). This technique could create a more profound insightin trigeminal anatomy, specifically concerning its intracerebralportion and is certain to contribute to clinical knowledge anddecision making in the daily practice of trigeminal neuropathies.Nevertheless issues regarding high resolution MRI and reliablequalitative probabilistic tracking of the trigeminothalamic tractsmay be important challenges to overcome (Jones et al., 2013).Beyond the challenges inherent in acquiring suitable DW-MRIdata, there are currently many obstacles to overcome regardingthe tractographic modeling of white matter tracts (O’Donnelland Pasternak, 2015). The use of post-mortem DTI could bea welcome supplement to the knowledge obtained by in vivofMRI-studies, in which the activation of regions of the braininvolved in the orofacial pain registration, have been mapped.There still remain outstanding questions that cannot be answeredtoday. Is it possible that the trigeminothalamic tracts in humansare more comparable to those in animals? Is it possible thatthe several nuclei of the TSNC are indeed part of a conjoinedcomplex which makes it difficult to separate several types ofsomatosensorical information and their conducting pathways?There is much left that we do not comprehend concerningorofacial pain, but knowledge of the involved trigeminothalamicand intranuclear pathways is believed to be of great importancein treating patients suffering from orofacial pain syndromeseffectively .

CONCLUSION

The main aim of this review was to present new insightsin trigeminal anatomy in humans, based on both animal-based papers and fMRI research studies. The classicalpoint of view is that orofacial pain is conducted in acontralateral fashion. However by synthesizing animal-based literature and human functional imaging studies,we state that the exact neuroanatomy of orofacial pain is






largely elusive, and we hypothesize the existence of a bilateralorofacial conduction system of nociceptive information inhumans.

ETHICAL STATEMENT

This study was carried out in accordance with therecommendations of the CMO (Commissie MensgebondenOnderzoek) region Arnhem-Nijmegen, Netherlands. Also, theprotocol was approved by the CMO region Arnhem-Nijmegen,Netherlands. The histological blockface in Figure 2 wasobtained from Mollink et al. (2015). This unpublishedhistological slice was acquired via the body donor programat the department of anatomy of the Radboud University

Medical Centre, Nijmegen, Netherlands. All body donors inthis program signed a written informed consent during lifetimepermitting the use of their body and parts for science andteaching.

AUTHOR CONTRIBUTIONS

DJHAH undertook the action of collecting the literature andwrote the first draft of the article. After collecting multiple timesthe input from A-MvCvW, EK and RvD, he wrote the otherversions. Together with EK, DJHAH created the Figures 2–4.Figure 1 was created by A-MvCvW and DJHAH. RHMAB andTK reviewed the latest versions and gave valuable input fromtheir point of expertise.

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Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.

Despite hosting a research topic together, the reviewer MH and handling Editorstate that the process met the standards of a fair and objective review.

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New Insights in Trigeminal Anatomy: A Double …...Keywords: trigeminal nerve, trigeminothalamic tract, orofacial pain, trigeminal neuropathy, bilateral registration INTRODUCTION Facial